This invention relates to compositions for use in delivery of bioactive agents to mucosal surfaces. The compositions provide increased bioavailability of the bioactive agents, particularly hydrophobic bioactive agents.
Oral delivery is the potentially most attractive route of bioactive agent delivery as it involves non-invasive techniques and enjoys a high patient compliance. The main drawback with oral delivery is the poor bioavailability of the vast majority of molecules via the gastrointestinal mucosa. Bioavailability refers to both the true rate and total amount (extent) of drug that reaches the general circulation from an administered dosage form.
Bioavailability is limited mainly by the dissolution and stability of the macromolecule in the milieu at the mucosal surface and the transport of the macromolecule across this surface (during absorption). While the former favours hydrophilic bioactive agents with increased dissolution in aqueous body fluids at the mucosal surface, the latter favours hydrophobic molecules which need to cross the apolar lipid bilayer of the cell membrane in order to enter the bloodstream. Bioavailability is also complicated by the non-aqueous behaviour of some mucosal surface milieus such as the amphipathic behaviour of lung surfactant at the pulmonary mucosal surface.
Hydrophobic bioactive agents in particular suffer from drawbacks in dosage formulation and bioavailability. Dosage formulations are often liquid, with the use of hydrophobic solvent such as oils or ethanol. Frequently, detergents are added to hydrophobic bioactive agent suspensions to enable formation of emulsions. Emulsions can improve bioavailability by placing the bioactive agent in suspension or a discontinuous array of droplets. Bioavailability from emulsion formulations is still limited. Intestinal mobility often moves these preparations past the absorption window in the proximal small bowel before these droplets or suspended particles are reduced in size sufficiently to be absorbed. Moreover, the manufacture and storage of emulsions is problematic due to phase separation and partitioning. A number of hydrophobic bioactive agents such as Cyclosporine A (CyA), Cephalosporins, amphotericins, griseofulvins, and other antifungals and antibiotics, taxols and vitamins would be improved by the formulation of dosage forms with increased bioavailability. The wide variety of bioactive agents includes, but is not limited to, those listed in Table 1.
One of the most frequently used hydrophobic bioactive agents, CyA is virtually insoluble in aqueous solvents and soluble in ethanol or fixed oils. The two most common dosage forms of CyA are administered as an oil formulation that must be formed into a microemulsion prior to absorption. These two formulations, Neoral(copyright) and Sandimmune(copyright) essentially differ in their bioavailability in that the former forms microemulsions more efficiently and this formulation shows significantly better bioavailability. GB Patent No. 2,257,359A. Neither formulation allows for a dry formulation such as a tablet or powder which would be of considerable benefit with respect to manufacture and storage of the drug.
CyA is of particular importance as it is being used not only as an immunosuppressant in transplant patients, but also as a treatment for asthma, dermatitis and arthritis. EP 577,544; EP 504,760 Tominaga et al. (1995) Gen. Pharmac. 26:353-356; and Arima et al. (1994) Jpn. J Allergol. 43:1316-1325. Dosage forms for treating asthma, other pulmonary conditions or for by-inhalation administration are most often in the form of aerosols of a fine mist of aqueous droplets. Several dosage forms and devices for by-inhalation delivery of hydrophobic bioactive agents have been described. These include small particle aerosol liposomes, aerosolized ethanol; and ultrasonic nebulizers. EP 267,050; EP 577,544; and Arima et al. (1994). More recently, the pulmonary administration of dry powders, driven by the need to eliminate aerosol propellants, has seen the development of many dry powder inhalers.
A variety of formulations have been provided for administration in aerosolized form to mucosal surfaces, particularly xe2x80x9cby-inhalationxe2x80x9d (nasopharyngeal and pulmonary). Compositions for by-inhalation pharmaceutical administration generally comprise a liquid formulation of the bioactive agent and a device for delivering the liquid in aerosolized form. U.S. Pat. No. 5,011,678 describes suitable compositions containing a pharmaceutically active substance, a biocompatible amphiphilic steroid and a biocompatible (hydro/fluor) carbon propellant. U.S. Pat. No. 5,006,343 describes suitable compositions containing liposomes, pharmaceutically active substances and an amount of alveolar surfactant protein effective to enhance transport of the liposomes across a pulmonary surface.
One drawback to the use of aerosolized formulations is that maintenance of pharmaceutical agents in aqueous suspensions or solutions can lead to aggregation and loss of activity and bioavailability. The loss of activity can be partially prevented by refrigeration; however, this limits the utility of these formulations. This is particularly true in the case of peptides and hormones. For instance, synthetic gonadotropin releasing hormone analogs, such as the agonist nafarelin or the antagonist ganirelex, are designed for high potency, increased hydrophobicity and membrane binding. The compounds have sufficient hydrophobic character to aggregate in aqueous solution and to form an ordered structure that increases in viscosity with time. Thus, bioavailability in nasal or pulmonary formulations can be prohibitively low.
The invention encompasses methods of making compositions with increased bioavailability for mucosal delivery of bioactive agents. The invention further comprises the compositions obtained thereby. In one embodiment, the compositions contain bioactive agents and hydrophobically-derivatized (substituted) carbohydrates (HDCS) in powder form. In another embodiment, the dosage forms contain bioactive agents, HDCs and surfactants in powder form. The compositions form solid solutions, suspensions or emulsions of bioactive agents, with or without modifiers and/or other additives, in an HDC glass.
The invention also encompasses methods of making compositions of suspensions of bioactive agents in aqueous solvents and the compositions obtained thereby. The methods include obtaining the compositions described above and dispersing the glass in an aqueous solvent suitable for administration. The compositions obtained thereby are also suitable for use as a solid dose form.
The compositions described herein are also suitable for delivery of pharmaceutical agents, particularly hydrophobic agents, as well as other biologically active agents such as flavourings, dyes, pesticides and cosmetics.